The present disclosure relates to a novel, cost-effective process for preparation of a 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1-a]isoquinoline derivatives. Specifically, it relates to a process for the preparation of praziquantel involving new intermediate.
Praziquantel of formula I, having the chemical name 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline, is a member of the 2-acyl-4-oxopyrazinoisoquinoline compounds, which are used as drugs for the treatment of a variety of worm infections. Praziquantel is primarily used against parasites known as “cestodes” and it is also effective against flukes.

There are number of literature references which describe the process for preparation of praziquantel. U.S. Pat. No. 4,001,411 describes a process for preparation of praziquantel by acylating 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline with cyclohexanoylchloride in chloroform and triethylamine.
KR2002076486 describes a process for preparation of praziquantel by reacting phenylethylamine with chloroacetyl chloride to obtain 2-chloro-N-phenethylacetamide. The compound 2-chloro-N-phenethylacetamide is then reacted with pthalimide to give 2-pthalimido-N-phenethylacetamide, which is then treated with hydrazine monohydrate to give 2-amino-N-phenylethylacetamide. On further treatment with bromoacetal, 2-amino-N-phenylethylacetamide gives 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide. This compound on further cyclization and acylation using cyclohexanoylchloride forms praziquantel.
CN1683346 describes a similar above process except the first step where 2-amino-N-phenylethylacetamide is prepared by reacting 2-aminoacetylchloride hydrochloride with phenylethylamine.
WO2009115333 describes many processes in one of which 3-phenylpropanenitrile is reacted with aminoacetal in presence of formaldehyde to obtain 2-[(2,2-dialkoxyethyl)amino]-N-(2-phenylethyl)acetamide, which is further cyclised and acylated using cyclohexanoylchloride to form praziquantel.
Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).
A major drawback in above the known processes is the use of aminoacetaldehyde dimethylacetal, a very expensive raw material. Moreover, it is used in two equivalents, with one equivalent being consumed in the reaction and the other equivalent being lost. It poses a lot of concern in terms of cost at the commercial scale production.
Thus there is a need to develop a process for the preparation of Praziquantel, which is cost effective and easy to handle on a commercial scale. In particular, there is a need to develop a process which avoids the use of costly aminoacetaldehyde dimethylacetal compounds to reduce the overall cost of production.
Thus, the present disclosure provides a cost effective process for preparing Praziquantel in good yield and good purity on a commercial scale.